Inhibitory effect of dietary iron deficiency on inductions of putative preneoplastic lesions as well as 8-hydroxydeoxyguanosine in DNA and lipid peroxidation in the livers of rats caused by exposure to a choline-deficient L-amino acid defined diet

Abstract

Effects of dietary iron deficiency on inductions of putative preneoplastic lesions and oxidative alterations in the livers of rats by a choline-deficient L-amino acid defined (CDAA) diet were examined. Male Fischer 344 rats, 4 weeks old, were used with a total experimental period of 16 weeks, consisting of 4-week pretreatment and 12-week treatment periods (periods A and B respectively). During period A, a choline-supplemented L-amino acid defined (CSAA) or an iron-deficient CSAA diet was administered, and the CDAA or an iron-deficient CDAA diet was fed in period B. Formation of 8-hydroxydeoxyguanosine (8OHdG), a DNA adduct generated by activated oxygen species, in DNA and lipid peroxidation in liver cell membranes were sequentially determined after the beginning of period B. At the end of the experiment, development of gamma-glutamyltransferase (GGT) and glutathione S-transferase placental form (GSTP) positive liver lesions were quantitatively analysed. In the animals fed the CDAA diet, formation of 8OHdG and lipid peroxidation increased with time, and GGT and GSTP positive liver lesions developed. Formation of 8OHdG, lipid peroxidation and the numbers of induced enzyme-altered liver lesions were all reduced in rats fed the iron-deficient CSAA diet in period A and/or the iron-deficient CDAA diet in period B. The present results indicate that iron plays an important role in induction of preneoplastic liver lesions in rats caused by exposure to the CDAA diet possibly in connection with its known catalytic role in generation of highly reactive activated oxygen species.

Age and Organ Dependent Spontaneous Generation of Nuclear 8-Hydroxydeoxyguanosine in Male Fischer 344 Rats

“…DNA hydrolysis and microfiltration of the resultant samples were subsequently conducted by the method of Helbock et al (1999). The levels of 8-OHdG were then determined by an adaptation of the HPLC-ECD method of Kasai et al (1987) as described elsewhere (Nakae et al, 1994a;Yoshiji et al, 1992). Peaks gained with electrochemical (for 8-OHdG) and UV (for dG) detectors were integrated with a background noise correction loaded on an integrator.…”

Fibrosis Accelerates the Development of Enzyme–Altered Lesions in the Rat Liver

“…associated hepatocyte damage and leads to proliferation with fibrosis, resulting in the development of enzyme-altered lesions. 7,8 The sequence of cellular changes in the liver proceeds from hepatocytes to enzyme-altered foci and then to hepatocellular neoplasm. 15 Thus, the induction of enzymealtered foci or nodules can serve as an indicator of preneoplastic change.…”

“…In particular, GSTP-positive lesions have been used as a marker of preneoplastic lesions, [16][17][18] and the extent of GSTP-positive lesions parallels the generation of 8OHdG (8-hydroxydeoxyguanosine) in DNA, which appears to be the major molecular lesion caused by a CDAA diet. 8 Increased hepatic MDA production after pretreatment with pig serum and feeding of a CDAA diet for 6 weeks suggests more DNA damage in the liver. But further determination of 8OHdG formation in future studies is necessary.…”

“…With regard to hepatocarcinogenesis induced by dietary choline deficiency in rats, induction of DNA lesions as well as lipid peroxidation of the inner nuclear, microsomal and mitochondrial membranes has been demonstrated. [5][6][7][8] Preneoplastic (GSTP-positive) lesions have also been correlated with DNA damage in this model. 8 Repeated intraperitoneal administration of pig serum to rats has been established as a model of liver fibrosis without hepatocyte cell death and proliferation.…”

“…[5][6][7][8] Preneoplastic (GSTP-positive) lesions have also been correlated with DNA damage in this model. 8 Repeated intraperitoneal administration of pig serum to rats has been established as a model of liver fibrosis without hepatocyte cell death and proliferation. [9][10][11][12] Activated stellate cells, which are positive for ␣ smooth muscle actin (␣SMA), play a key role in the development of fibrosis in experimental models as well as in human liver disease.…”